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Diseases, disorders, and insults of aging are frequently studied in otherwise healthy animal models despite rampant co-morbidities and exposures among the human population. Stressor exposures can increase neuroinflammation and augment the... more
Diseases, disorders, and insults of aging are frequently studied in otherwise healthy animal models despite rampant co-morbidities and exposures among the human population. Stressor exposures can increase neuroinflammation and augment the inflammatory response following a challenge. The impact of dietary exposure on baseline neural function and behavior has gained attention; in particular, a diet high in fructose can increase activation of the hypothalamic-pituitary-adrenal axis and alter behavior. The current study considers the implications of a diet high in fructose for neuroinflammation and outcomes following the cerebrovascular challenge of stroke. Ischemic injury may come as a “second hit” to pre-existing metabolic pathology, exacerbating inflammatory and behavioral sequelae. This study assesses the neuroinflammatory consequences of a peri-adolescent high-fructose diet model and assesses the impact of diet-induced metabolic dysfunction on behavioral and neuropathological outcomes after middle cerebral artery occlusion. We demonstrate that consumption of a high-fructose diet initiated during adolescent development increases brain complement expression, elevates plasma TNFα and serum corticosterone, and promotes depressive-like behavior. Despite these adverse effects of diet exposure, peri-adolescent fructose consumption did not exacerbate neurological behaviors or lesion volume after middle cerebral artery occlusion.
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BACKGROUND: Tissue plasminogen activator (tPA) is the only FDA-approved treatment for acute stroke. Unfortunately, because of its narrow time window and high risk-to-benefit ratio it is used in less than 3.0% of stroke patients. Our group... more
BACKGROUND: Tissue plasminogen activator (tPA) is the only FDA-approved treatment for acute stroke. Unfortunately, because of its narrow time window and high risk-to-benefit ratio it is used in less than 3.0% of stroke patients. Our group and others have shown progesterone (PROG) to be beneficial in several ischemic brain injury models. However, before PROG can be tested in stroke patients, how it will interact with tPA, and whether combination with PROG will increase or decrease the risk of bleeding and hemorrhagic conversion, should be determined. In the present study we examined whether PROG would prevent tPA associated hemorrhagic transformation in an experimental stroke model. PROG’s efficacy in preventing tPA-induced impairment of transendothelial electrical resistance (TEER) under hypoxia/reoxygenation (H/R) conditions was evaluated in a mouse brain endothelial cell line. METHODS: Male SD rats were subjected to right middle cerebral artery occlusion (MCAO), reperfused at 4.5 hours and then treated with tPA (5 mg/kg b.wt; via femoral vein) at 4.5 hours or PROG (intraperitoneally) at 2 hours plus tPA at 4.5 hours. Rats were killed at 24 hours post-ischemia and brains perfused for evaluation of cerebral hemorrhage, brain swelling, blood-brain barrier (BBB) permeability, MMP-9 activity and cerebral infarction. TEER across the endothelial cell membrane was measured using an EVOM resistance meter. RESULTS: Delayed tPA treatment induced significant (p<0.05) hemorrhagic conversion and brain swelling. Combining PROG with delayed tPA administration significantly ameliorated brain hemorrhage, hemispheric swelling, BBB permeability and MMP-9 induction compared to the saline-treated injured group. The reduction in hemorrhagic injury in PROG+tPA-treated rats was 59.0% compared to tPA-treated rats without PROG. PROG treatment also significantly prevented the decrease in TEER induced by tPA under H/R conditions in vitro . CONCLUSIONS: Our data can be taken to suggest that PROG administration may extend the therapeutic time window for tPA administration in ischemic stroke, while at the same time reducing the risk of hemorrhagic conversion.
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Twenty-month-old male Fischer 344 rats with bilateral contusions of the frontal cortex (n=8/group) or sham operations received 16 mg/kg of progesterone or vehicle at 1 and 6 h post-injury, then once every 24 h for the next seven days,... more
Twenty-month-old male Fischer 344 rats with bilateral contusions of the frontal cortex (n=8/group) or sham operations received 16 mg/kg of progesterone or vehicle at 1 and 6 h post-injury, then once every 24 h for the next seven days, with tapering of the dose over the final two treatments. The rats' behavioral recovery was then evaluated on tests of locomotor activity and Morris water maze learning. All rats were sacrificed 21 days post-TBI and brains were perfused and cryoprotected for necrotic cavity measurements. The injury produced significant impairments in activity and spatial learning compared to sham controls. The progesterone-treated rats had better functional outcomes than vehicle-treated rats with similar cortical injuries. The neurosteroid treatment did not affect the size of the necrotic cavity.
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The poor aqueous solubility of progesterone (PROG) limits its potential use as a therapeutic agent. We designed and tested EIDD-1723, a novel water-soluble analog of PROG with >100-fold higher solubility... more
The poor aqueous solubility of progesterone (PROG) limits its potential use as a therapeutic agent. We designed and tested EIDD-1723, a novel water-soluble analog of PROG with >100-fold higher solubility than that of native PROG, as candidate for development as a field-ready treatment for traumatic brain injury (TBI). The pharmacokinetic effects of EIDD-1723 on morphological and functional outcomes in rats with bilateral cortical impact injury were evaluated. Following TBI, 10-mg/kg doses of EIDD-1723 or PROG were given intramuscularly (i.m.) at 1, 6 and 24 h post-injury, then daily for the next 6 days, with tapering of the last 2 treatments. Rats were tested pre-injury to establish baseline performance on grip strength and sensory neglect, and then retested at 4, 9 and 21 days post-TBI. Spatial learning was evaluated from days 11-17 post-TBI. At 22 days post-injury, rats were perfused and brains extracted and processed for lesion size. For the edema assay the animals were killed and brains removed at 24 h post-injury. EIDD-1723 significantly reduced cerebral edema and improved recovery from motor, sensory and spatial learning deficits as well as, or better than, native PROG. Pharmacokinetic investigation after a single i.m. injection in rats revealed that EIDD-1723 was rapidly converted to the active metabolite EIDD-036, demonstrating first-order elimination kinetics and ability to cross the blood-brain barrier. Our results suggest that EIDD-1723 represents a substantial advantage over current PROG formulations because it overcomes storage, formulation and delivery limitations of PROG and can thereby reduce the time between injury and treatment.
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Purpose: Previous studies suggest that progesterone (PROG) has a substantial protective effect against several types of brain injury. Since most cases of human stroke are caused by permanent occlusion of cerebral arteries, we assessed the... more
Purpose: Previous studies suggest that progesterone (PROG) has a substantial protective effect against several types of brain injury. Since most cases of human stroke are caused by permanent occlusion of cerebral arteries, we assessed the neuroprotective effects of PROG on cerebral infarction and behavioral deficits in a permanent MCAO (pMCAO) model. Methods: pMCAO was produced by surgical insertion of a silicone-coated nylon filament into the right internal carotid artery. Laser-Doppler flowmetry was used to monitor cerebral blood flow for 10 min post-occlusion. PROG (8 mg/kg) or vehicle (2-hydroxypropyl-beta-cyclodextrin) was administered intraperitoneally at 1 h post-occlusion followed by subcutaneous injections at 6, 24 and 48 h post-occlusion. Measurements of infarct volumes (cortical, subcortical and total) were performed at 72 h and functional recovery, assessed by rotarod test, were performed 24, 48, and 72 h after pMCAO. Results: Following PROG treatment, stained sections revealed a significant reduction in cortical, caudate-putamen and hemispheric infarct volumes (% contralateral structure) compared to vehicle-injected controls. In addition, PROG treatment reduced functional deficits on the accelerating rotarod apparatus. Conclusion: We demonstrated and confirmed the neuroprotective effect of PROG using a permanent model of focal brain ischemia in rats.
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Research Interests: Psychology, Biology, Medicine, Ischemia, Animals, and 15 moreMale, Retina, Brain Ischemia, Retinal, Clinical Sciences, Eye, Rats, Glial Fibrillary Acidic Protein, Experimental Neurology, Retinal Diseases, Glutamine Synthetase, Neurosciences, Extracellular Space, Glutamic Acid, and Severity of Illness Index
Despite hundreds of positive preclinical studies and two successful Phase II clinical trials, two large Phase III trials of progesterone treatment for traumatic brain injury were recently ended with no finding of any difference between... more
Despite hundreds of positive preclinical studies and two successful Phase II clinical trials, two large Phase III trials of progesterone treatment for traumatic brain injury were recently ended with no finding of any difference between the test drug and placebo. This chapter discusses some possible reasons for this outcome and proposes returning to Phase II and using a more effective clinical trial design. Specifically, we propose dose and duration of treatment optimization following allometric scaling principles to convert rat mg/kg/day dose to the appropriate human dose. We also propose to verify that the vehicle, at the concentration needed for patients, does not have antiinflammatory or neuroprotective clinical effects. Finally, preclinical animal studies should be conducted to determine whether the lipid vehicles used might alter the drug effects at the required concentrations.
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Introduction: Cerebral ischemia, a consequence of cardiac arrest and stroke, is a leading cause of death and disability in the U.S. To improve translational studies, STAIR recommends augmenting animal models with comorbidities that... more
Introduction: Cerebral ischemia, a consequence of cardiac arrest and stroke, is a leading cause of death and disability in the U.S. To improve translational studies, STAIR recommends augmenting animal models with comorbidities that “better reproduce the pathophysiological state” of stroke patients. Therefore, we incorporated social stress into our ischemia model (Espinosa-Garcia et al., 2017). Prior exposure to social stress upregulates the inflammatory status of microglia. They become primed—sensitized to activation by subsequent ischemia—worsening outcome. Such potentiated activation may result from the release of danger signals in the brain, such as HMGB-1, which binds to TLR4 receptors and activates inflammasomes. The NLRP3 inflammasome consists of a sensor molecule, NLRP3, the ASC adaptor, and caspase-1, whose activation leads to pro-inflammatory IL-1β production. We hypothesized that progesterone (P4) administration will reduce NLRP3 inflammasome activation, one of the molecul...
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Cerebral ischemia/reperfusion (I/R) induces in situ inflammatory responses which contribute to further brain injury. Toll-like receptors (TLRs) are a trans-membrane, pattern-recognition receptor family with important roles in the... more
Cerebral ischemia/reperfusion (I/R) induces in situ inflammatory responses which contribute to further brain injury. Toll-like receptors (TLRs) are a trans-membrane, pattern-recognition receptor family with important roles in the induction and regulation of immune/inflammatory responses. TLR4 is known to be involved in cerebral I/R injury and is considered a potential target for the treatment of ischemic stroke. This experiment evaluated the hypothesis that an exogenous TLR4 antagonist, TAK-242, protects brain from I/R injury. A mouse model of cerebral I/R was induced by transient middle cerebral artery occlusion (tMCAO). TAK-242 (3 mg/kg body weight) was intraperitoneally injected (i.p.) 1 hour after ischemia. Concentrations of TAK-242 in plasma and brain tissue were measured 3, 8, and 24 hrs after injection. Neurological scores were evaluated 24 hrs after cerebral I/R. Brain infarct areas were detected by TTC staining. Inflammatory cytokines were analyzed by antibody arrays 6 hrs ...
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Background: Growing evidence suggests that Vitamin D hormone deficiency (VDH def ) is a risk factor for ischemic stroke and its severity. Blood-brain barrier (BBB) impairment is a marker of secondary cerebral injury following stroke and... more
Background: Growing evidence suggests that Vitamin D hormone deficiency (VDH def ) is a risk factor for ischemic stroke and its severity. Blood-brain barrier (BBB) impairment is a marker of secondary cerebral injury following stroke and is associated with an increased propensity for hemorrhage. Our in vitro work showed that VDH treatment reduces BBB damage after hypoxia/reperfusion injury via VDR-mediated NF-kB-MMP9 pathways. We explored the role of VDH in maintaining BBB integrity in a rodent model of stroke. Methods: Male Wistar rats (n=48) were assigned to one of two diet cohorts, VDH-sufficient (VDH suf ) and VDH def . The VDH suf group was fed standard chow and the VDH def group was fed a VDH-null version of the same diet for 8 weeks. Animals from both cohorts received either sham or transient middle cerebral artery occlusion (tMCAO) surgeries and were assigned to one of 4 groups (n=12/group): sham VDH suf , MCAO+VDH suf , Sham+VDH def , or MCAO+VDH def . Rats were killed at 72...
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BACKGROUND Evidence from animal models and human studies suggests an association between early general anaesthesia exposure and development of long-lasting neurocognitive problems including learning and memory impairments and an anxious... more
BACKGROUND Evidence from animal models and human studies suggests an association between early general anaesthesia exposure and development of long-lasting neurocognitive problems including learning and memory impairments and an anxious phenotype. Because millions of children each year undergo procedures that require anaesthesia, it is important to investigate ways to protect the vulnerable developing brain. We evaluated whether progesterone treatment administered before general anaesthesia exposure could prevent long-term anaesthesia-induced neurocognitive and behavioural changes. METHODS Female and male Long-Evans rat pups were repeatedly exposed to 2 h of sevoflurane or control procedures at postnatal days 7, 10, and 13. Subcutaneous injections of progesterone or vehicle were administered immediately before general anaesthesia exposure or control procedures. Neurobehavioural and cognitive outcomes were evaluated using elevated plus maze and Morris water maze tests. RESULTS Prophylactic progesterone treatment attenuated the chemokine (C-X-C motif) ligand 1 (CXCL1) response to sevoflurane exposure. Rats given vehicle treatment with general anaesthesia exposure exhibited increased anxiety on the elevated plus maze and learning and memory impairments on the Morris water maze. However, rats treated with progesterone before general anaesthesia lacked these impairments and performed in a similar manner to controls on both tasks. CONCLUSIONS Progesterone attenuated the anaesthesia-induced, acute peripheral inflammatory response and prevented cognitive and behavioural alterations associated with early repeated general anaesthesia exposure. Importantly, our results suggest that progesterone treatments given before general anaesthesia may help to protect the developing brain.
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Introduction: Stress is associated with increased risk of stroke and poor prognosis, but the mechanisms through which stress may alter stroke outcome remain elusive. Stress compromises neuronal survival and neuroinflammation following an... more
Introduction: Stress is associated with increased risk of stroke and poor prognosis, but the mechanisms through which stress may alter stroke outcome remain elusive. Stress compromises neuronal survival and neuroinflammation following an ischemic attack. Post-ischemic inflammatory response involves the activation of microglia, which can be polarized from a harmful M1 phenotype which expresses pro-inflammatory cytokines, to a protective M2 phenotype which releases neurotrophic factors. We hypothesize that progesterone (PROG) will improve global ischemia outcome by modulating microglial polarization in stressed ischemic animals. Methods: Adult male rats were exposed to social defeat stress over 8 consecutive days. Then, rats were subjected to 8 min of global ischemia by the four-vessel occlusion model. PROG (8 mg/Kg/b.w.) was administered by intraperitoneal injection at 2 h post-ischemia followed by subcutaneous injections at 6 h and once every 24 h post-injury for 5 days, and then 2 ...
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NOD-like receptor pyrin domain containing 3 (NLRP3) inflammasome inhibition and autophagy induction attenuate inflammation and improve outcome in rodent models of cerebral ischemia. However, the impact of chronic stress on NLRP3... more
NOD-like receptor pyrin domain containing 3 (NLRP3) inflammasome inhibition and autophagy induction attenuate inflammation and improve outcome in rodent models of cerebral ischemia. However, the impact of chronic stress on NLRP3 inflammasome and autophagic response to ischemia remains unknown. Progesterone (PROG), a neuroprotective steroid, shows promise in reducing excessive inflammation associated with poor outcome in ischemic brain injury patients with comorbid conditions, including elevated stress. Stress primes microglia, mainly by the release of alarmins such as high-mobility group box-1 (HMGB1). HMGB1 activates the NLRP3 inflammasome, resulting in pro-inflammatory interleukin (IL)-1β production. In experiment 1, adult male Sprague-Dawley rats were exposed to social defeat stress for 8 days and then subjected to global ischemia by the 4-vessel occlusion model, a clinically relevant brain injury associated with cardiac arrest. PROG was administered 2 and 6 h after occlusion and...
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Introduction: Exposure to stress primes microglia and the NLRP3 inflammasome, resulting in an exaggerated inflammatory response to a secondary insult such as stroke. NLRP3-mediated inflammation can be regulated by the autophagic removal... more
Introduction: Exposure to stress primes microglia and the NLRP3 inflammasome, resulting in an exaggerated inflammatory response to a secondary insult such as stroke. NLRP3-mediated inflammation can be regulated by the autophagic removal of inflammasome activators, components, or cytokines. We hypothesized that progesterone (PROG), a neuroprotective neurosteroid, would enhance autophagy in a rodent model of cerebral ischemia combined with stress, and in an in vitro inflammasome assay. Methods: Adult male rats were exposed to social defeat stress for 8 days and then subjected to global ischemia. PROG (8 mg/Kg) was administered 2 and 6 h after occlusion, then daily for 7 days. At 7 and 14 days post-ischemia, hippocampi were dissected and autophagic flux was evaluated by western blot using LC3-II and p62 as indicators. To activate the NLRP3 inflammasome in vitro , cultured primary mouse microglia were primed with 1 ug/mL LPS for 2 h prior to stimulation with 5 mM ATP (a classical inflam...
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BACKGROUND: Previously we carried out a dose response study and reported 8 mg/kg PROG to be the optimal therapeutic dose following in pMCAO. A systematic preclinical progesterone (PROG) therapeutic time window study is lacking. In the... more
BACKGROUND: Previously we carried out a dose response study and reported 8 mg/kg PROG to be the optimal therapeutic dose following in pMCAO. A systematic preclinical progesterone (PROG) therapeutic time window study is lacking. In the present study we used a clinically relevant middle-aged rat and long-term sensory, motor, and cognitive outcome measures to determine the effects of delayed PROG treatment. METHODS: Male Sprague-Dawley rats (12 months old) underwent pMCAO by electrocoagulation or sham operation. Beginning 3, 6, or 24 h post-occlusion, rats were given IP injections of 8 mg/kg of PROG or vehicle, followed by SC injections at 5 h after the first IP injection and then every 24 h for 7 days. The dose was tapered over the final 2 treatments. Behavioral recovery was evaluated at repeated intervals on sensory, motor, and cognitive tasks. Rats were killed at 22 days post-stroke and brains perfused for infarct evaluation. RESULTS: Three weeks post-pMCAO, PROG treatment delayed b...
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BACKGROUND: There is currently no safe, effective, widely applicable post-stroke treatment for ischemic stroke, especially when treatment is delayed beyond a few hours. Our group and others have shown progesterone (PROG) to be beneficial... more
BACKGROUND: There is currently no safe, effective, widely applicable post-stroke treatment for ischemic stroke, especially when treatment is delayed beyond a few hours. Our group and others have shown progesterone (PROG) to be beneficial after brain injury in several injury models. A systematic pre-clinical PROG dose-response study in ischemic stroke models is lacking. Since focal pMCAO models better simulate the typical human stroke injury without reperfusion, our study sought to determine PROG's dose-response effects on behavioral performance after pMCAO. We used a clinically relevant, middle-aged rat model and long-term sensory, motor, and cognitive outcome measures. METHODS: Male Sprague-Dawley rats (12 months old) underwent pMCAO by electrocoagulation or sham operation. At 1h post-pMCAO, the animals were given an intraperitoneal injection of one of three doses of PROG (8, 16, or 32 mg/kg), followed by subcutaneous injections 6h post-injury and then once every 24h for the ne...
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BACKGROUND: Less is known about the long-term sustained effects of PROG on recovery of function following stroke. Two objectives were evaluated, First, whether functional deficits caused by pMCAO persist and if repeated testing in itself... more
BACKGROUND: Less is known about the long-term sustained effects of PROG on recovery of function following stroke. Two objectives were evaluated, First, whether functional deficits caused by pMCAO persist and if repeated testing in itself reduce the extent of injury over long periods (8 weeks). Second, determine PROG's effects on a panel of behavioral tests performed several weeks post-pMCAO Methods: Male Sprague-Dawley rats (12 months old) underwent pMCAO by electrocoagulation or sham surgery. For the first study, repeated long term group with pMCAO began a battery of tests at repeated intervals (during the 3rd, 6th, and 8th weeks post-pMCAO), while long term with pMCAO group testing began during the 8 th week post-pMCAO. For the second study, beginning 3 h post-occlusion, rats were given IP injections of 8 mg/kg of PROG or vehicle, followed by SC injections at 8 h and then every 24 h for 9 days with tapering of final 2 treatments. All animals received: motor, sensory and cognit...
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Although progesterone is critical to a healthy pregnancy, it is now known to have other important functions as well. Recent research demonstrates that this hormone is also a potent neurosteroid that can protect damaged cells in the... more
Although progesterone is critical to a healthy pregnancy, it is now known to have other important functions as well. Recent research demonstrates that this hormone is also a potent neurosteroid that can protect damaged cells in the central and peripheral nervous systems and has rapid actions that go well beyond its effects on the classical intranuclear progesterone receptor. Based on years of preclinical research demonstrating its safety and effectiveness in animal models of central nervous system injury the hormone was recently tested in two Phase II clinical trials for traumatic brain injury (TBI). A US National Institutes of Health-sponsored, nationwide Phase III clinical trial is now evaluating progesterone for moderate-to-severe TBI in 1200 patients. An industry-sponsored Phase III international trial is also under way, and planning for a trial using progesterone to treat pediatric brain injury has begun. Preclinical data suggest that progesterone may also be effective in strok...
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As a follow-up to the 2008 state-of-the-art (SOTA) conference on traumatic brain injuries (TBIs), the 2015 event organized by the United States Department of Veterans Affairs (VA) Office of Research and Development (ORD) analysed the... more
As a follow-up to the 2008 state-of-the-art (SOTA) conference on traumatic brain injuries (TBIs), the 2015 event organized by the United States Department of Veterans Affairs (VA) Office of Research and Development (ORD) analysed the knowledge gained over the last 7 years as it relates to basic scientific methods, experimental findings, diagnosis, therapy, and rehabilitation of TBIs and blast-induced neurotraumas (BINTs). The current article summarizes the discussions and recommendations of the scientific panel attending the Preclinical Modeling and Therapeutic Development Workshop of the conference, with special emphasis on factors slowing research progress and recommendations for ways of addressing the most significant pitfalls.
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Goldstein et al.'s Secondary Analysis of Progesterone Clinical Trial for Traumatic Brain Injury Can Only Reflect the Same Trial Design Flaws: A Response to "Very Early Administration of Progesterone Does Not Improve Neuropsychological Outcomes in Subjects with Moderate to Severe Traumatic Brain I...more
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The most important aspect of a preclinical study seeking to develop a novel therapy for neurological diseases is whether the therapy produces any clinically relevant functional recovery. For this purpose, neurobehavioral tests are... more
The most important aspect of a preclinical study seeking to develop a novel therapy for neurological diseases is whether the therapy produces any clinically relevant functional recovery. For this purpose, neurobehavioral tests are commonly used to evaluate the neuroprotective efficacy of treatments in a wide array of cerebrovascular diseases and neurotrauma. Their use, however, has been limited in experimental subarachnoid hemorrhage studies. After several randomized, double-blinded, controlled clinical trials repeatedly failed to produce a benefit in functional outcome despite some improvement in angiographic vasospasm, more rigorous methods of neurobehavioral testing became critical to provide a more comprehensive evaluation of the functional efficacy of proposed treatments. While several subarachnoid hemorrhage studies have incorporated an array of neurobehavioral assays, a standardized methodology has not been agreed upon. Here, we review neurobehavioral tests for rodents and th...
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The poor aqueous solubility of progesterone (PROG) limits its potential use as a therapeutic agent. We designed and tested EIDD-1723, a novel water-soluble analog of PROG with >100-fold higher solubility than that of native PROG, as... more
The poor aqueous solubility of progesterone (PROG) limits its potential use as a therapeutic agent. We designed and tested EIDD-1723, a novel water-soluble analog of PROG with >100-fold higher solubility than that of native PROG, as candidate for development as a field-ready treatment for traumatic brain injury (TBI). The pharmacokinetic effects of EIDD-1723 on morphological and functional outcomes in rats with bilateral cortical impact injury were evaluated. Following TBI, 10-mg/kg doses of EIDD-1723 or PROG were given intramuscularly (i.m.) at 1, 6 and 24 h post-injury, then daily for the next 6 days, with tapering of the last 2 treatments. Rats were tested pre-injury to establish baseline performance on grip strength and sensory neglect, and then retested at 4, 9 and 21 days post-TBI. Spatial learning was evaluated from days 11-17 post-TBI. At 22 days post-injury, rats were perfused and brains extracted and processed for lesion size. For the edema assay the animals were killed...
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Research Interests: Neuroscience, Cognition, Apoptosis, Medicine, Prefrontal Cortex, and 15 moreCaspases, Learning and Memory, Progesterone, Animals, Male, Cell Death, Brain injury, Caspase, Nervous System, Neurosciences, Enzyme Linked Immunosorbent Assay, Neuroprotective Agents, DNA fragmentation, Phosphate Buffer Saline, and Brain injuries
Although progress is being made in the development of new clinical treatments for traumatic brain injury (TBI), little is known about whether such treatments are effective in older patients, in whom frailty, prior medical conditions,... more
Although progress is being made in the development of new clinical treatments for traumatic brain injury (TBI), little is known about whether such treatments are effective in older patients, in whom frailty, prior medical conditions, altered metabolism, and changing sensitivity to medications all can affect outcomes following a brain injury. In this review we consider TBI to be a complex, highly variable, and systemic disorder that may require a new pharmacotherapeutic approach, one using combinations or cocktails of drugs to treat the many components of the injury cascade. We review some recent research on the role of vitamin D hormone and vitamin D deficiency in older subjects, and on the interactions of these factors with progesterone, the only treatment for TBI that has shown clinical effectiveness. Progesterone is now in phase III multicenter trial testing in the United States. We also discuss some of the potential mechanisms and pathways through which the combination of hormon...
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Systemic injections of GM1 gangliosides can enhance behavioral recovery from brain damage as measured by a number of cognitive tasks. The functional recovery is not due to GM1-induced alterations in activity, emotional arousal, or... more
Systemic injections of GM1 gangliosides can enhance behavioral recovery from brain damage as measured by a number of cognitive tasks. The functional recovery is not due to GM1-induced alterations in activity, emotional arousal, or heightened sensitivity to mild, noxious stimulation. In addition, the recovery endures long after all treatments are terminated. Although the specific actions by which GM1 treatments facilitate recovery are unknown, evidence does suggest that both anomalous sprouting and protection of neurons from secondary consequences of injury may be involved in the repair process.